Protective and Antioxidant Effects of PPARα in the Ischemic Retina

Abstract

PURPOSE. Previous studies have demonstrated that peroxisome proliferator-activated receptoralpha (PPARa) agonists have therapeutic effects in diabetic retinopathy, although the mechanism of action remains incompletely understood. The purpose of this study was to evaluate PPARa's protective effects in the ischemic retina, and to delineate its molecular mechanism of action. METHODS.For the oxygen-induced retinopathy (OIR) model, wild-type (WT), and PPARa knockout (PPARa À/À ) mice were exposed to 75% O 2 from postnatal day 7 (P7) to P12 and treated with the PPARa agonist fenofibric acid (Feno-FA) from P12 to P16. At P17, the effects of Feno-FA on retinal glial fibrillary acidic protein (GFAP) expression, apoptotic DNA cleavage, and TUNEL labeling were analyzed. Cultured retinal cells were exposed to CoCl 2 to induce hypoxia, and TUNEL staining and 5-(and-6)-chloromethyl-2 0 ,7 0 -dichlorodihydrofluorescein dye were used to measure apoptosis and reactive oxygen species (ROS) generation. Western blotting was used to measure GFAP levels and cell signaling. RESULTS. Feno-FA decreased retinal apoptosis and oxidative stress in WT but not PPARaÀ/À OIR mice. Peroxisome proliferator-activated receptor-alpha knockout OIR mice showed increased retinal cell death and glial activation in comparison to WT OIR mice. Feno-FA treatment and PPARa overexpression protected cultured retinal cells from hypoxic cell death and decreased ROS levels. Nuclear hypoxia-inducible factor-a (HIF-1a) and nicotine adenine dinucleotide phosphate oxidase-4 (Nox 4) were increased in OIR retinas and downregulated by Feno-FA in WT but not in PPARa À/À mice.CONCLUSIONS. Peroxisome proliferator-activated receptor-alpha has a potent antiapoptotic effect in the ischemic retina. This protective effect may be mediated in part through downregulation of HIF-1a/Nox 4 and consequently alleviation of oxidative stress.

Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects

“…PPARα −/− mice had increased retinal cell death and glial activation in OIR. Activation of PPARα by its ligand, fenofibric acid, inhibited OIR-induced Nox4 upregulation [76]. These findings support the line of thinking that activation of NOX4 regulates the interaction of vascular inflammatory and pathologic angiogenesis in diabetic retinopathy.…”

Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

“…The antioxidant effects of PPARα and its agonist have been reported in the retinae and kidneys of diabetic models by our group and others (8,19,44). We have reported (30) that enhanced oxidative stress contributed to the activation of the Wnt pathway in the retinae of diabetic rats via stabilizing LRP6.…”

Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis

“…The mechanism underlying the protective effect of fenofibrate on diabetic retinopathy is independent of its ability to initiate a peroxisome proliferator-activated receptor (PPAR) α-mediated lipid lowering effect (Bogdanov et al, 2015, Simo et al, 2015). There are no clinical studies on the effects of fenofibrate on other neovascular eye diseases, although fenofibrate has been shown to have a potent anti-apoptotic effect in the ischemic retina, to suppress ischemia-induced endothelial progenitor cell mobilization and homing, and to inhibit angiogenesis in vivo and in vitro (Moran et al, 2014, Wang et al, 2014, Varet et al, 2003). …”